Cancer incidence in World Trade Center rescue and recovery workers by race and ethnicity.

INTRODUCTION: It is unclear whether differences in health outcomes by racial and ethnic groups among World Trade Center (WTC) rescue and recovery workers reflect those of the population of New York State (NYS) or show distinct patterns. We assessed cancer incidence in WTC workers by self-reported race and ethnicity, and compared it to population figures for NYS. METHODS: A total of 61,031 WTC workers enrolled between September 11, 2001 and January 10, 2012 were followed to December 31, 2015. To evaluate the association between race/ethnicity and cancer risk, Poisson regression analysis was used to estimate hazard ratios (HR) adjusted for WTC exposure, age, calendar year, sex and, for lung cancer, cigarette smoking. RESULTS: In comparison to Whites, Black workers had a higher incidence of prostate cancer (HR = 1.99, 95% CI = 1.69-2.34) and multiple myeloma (HR = 3.57, 95% CI = 1.97-6.45), and a lower incidence of thyroid (HR = 0.41, 95% CI = 0.22-0.78) and colorectal cancer (HR = 0.57; 95% CI = 0.33-0.98). Hispanic workers had a higher incidence of liver cancer (HR = 4.03, 95% CI = 2.23-7.28). Compared with NYS population, White workers had significantly higher incidence of prostate cancer (HR = 1.26, 95% CI = 1.18-1.35) and thyroid cancer (HR = 1.80, 95% CI = 1.55-2.08), while Black workers had significantly higher incidence of prostate cancer (HR = 1.22, 95% CI = 1.05-1.40). CONCLUSION: Cancer incidence in WTC workers generally reflects data from the NYS population, but some differences were identified that merit further investigation.

A 15-year follow-up study of mortality in a pooled cohort of World Trade Center rescue and recovery workers.

INTRODUCTION: Hazardous exposures from the World Trade Center (WTC) terrorist attacks have been linked to increased incidence of adverse health conditions, often associated with increased mortality. We assessed mortality in a pooled cohort of WTC rescue/recovery workers over 15 years of follow-up. MATERIALS AND METHODS: We analyzed mortality through 2016 in a pooled and deduplicated cohort of WTC rescue/recovery workers from three WTC-exposed cohorts (N = 60,631): the Fire Department of the City of New York (FDNY); the WTC Health Registry (WTCHR); and the General Responder Cohort (GRC). Standardized mortality ratios (SMRs) were estimated to assess mortality vs. the US and NY state populations. Multivariable Cox proportional hazards models were used to examine associations of WTC exposures (date of first arrival, working on the WTC debris pile) with mortality risk. RESULTS: There were 1912 deaths over 697,943.33 person-years of follow-up. The SMR for all-cause mortality was significantly lower-than-expected, both when using US (SMR 0.43, 95% confidence interval [CI] 0.42-0.45) and NYS (SMR 0.51, 95% CI 0.49-0.53) as reference populations. SMRs were not elevated for any of the 28 major causes of death. Arriving at the WTC site on 9/11-9/17/2001 vs. 9/18/2001-6/30/2002 was associated with 30-50% higher risk of all-cause, heart disease and smoking-related mortality in non-FDNY/non-GRC members. Conversely, arriving on 9/11/2001 vs. 9/18/2001-6/30/2002 was associated with 40% lower all-cause and smoking-related mortality risk in FDNY members. Working on vs. off the WTC pile was associated with an increased risk of all-cause mortality in non-FDNY/non-GRC members (adjusted hazard ratio [aHR] 1.25, 95% CI 1.04-1.50), and cancer-specific mortality in GRC members (aHR 1.39, 95% CI 1.05-1.84), but lower mortality risks were found in FDNY members. CONCLUSIONS: We did not observe excess mortality among WTC rescue/recovery workers compared with general populations. However, significantly increased mortality risks among some sub-groups with high WTC exposure warrant further investigation.

Cancer risk among World Trade Center rescue and recovery workers: A review.

Twenty years after the September 11th, 2001 terrorist attacks, the association between exposures present at the World Trade Center (WTC) site and the risk of several specific types of cancer has been reported among rescue and recovery workers. The authors' objective was to conduct an updated review of these data. Most studies have found elevated rates of both prostate and thyroid cancers compared with rates in the general population, and some have reported statistically significant differences for the rates of all cancers as well. Studies including a larger combined cohort of WTC-exposed rescue and recovery workers from 3 main cohorts have since replicated findings for these cancers, with additional years of follow-up. Among this combined cohort, although a lower-than-expected standardized incidence ratio for all cancers was observed, WTC exposure was also related to an increased risk of cutaneous melanoma and tonsil cancer. Importantly, another study found that WTC-exposed rescue and recovery workers who are enrolled in the federally funded medical monitoring and treatment program experienced improved survival post-cancer diagnosis compared with New York state patients with cancer. On the basis of these combined cohort studies, the full effect of WTC exposure on cancer risk is becoming clearer. Consequently, the authors believe that surveillance of those with WTC exposure should be continued, and in-depth analysis of epidemiologic, molecular, and clinical aspects of specific cancers in these workers should be pursued.

Lung cancer incidence among world trade center rescue and recovery workers.

BACKGROUND: Many World Trade Center disaster (WTC) rescue and recovery workers (WTC RRWV) were exposed to toxic inhalable particles. The impact of WTC exposures on lung cancer risk is unclear. METHODS: Data from the WTC Health Program General Responders Cohort (WTCGRC) were linked to health information from a large New York City health system to identify incident lung cancer cases. Incidence rates for lung cancer were then calculated. As a comparison group, we created a microsimulation model that generated expected lung cancer incidence rates for a WTC- and occupationally-unexposed cohort with similar characteristics. We also fitted a Poisson regression model to determine specific lung cancer risk factors for WTC RRWV. RESULTS: The incidence of lung cancer for WTC RRWV was 39.5 (95% confidence interval [CI]: 30.7-49.9) per 100,000 person-years. When compared to the simulated unexposed cohort, no significant elevation in incidence was found among WTC RRWV (incidence rate ratio [IRR] 1.34; 95% CI: 0.92-1.96). Predictors of lung cancer incidence included age, smoking intensity, and years since quitting for former smokers. In adjusted models evaluating airway obstruction and individual pre-WTC occupational exposures, only mineral dust work was associated with lung cancer risk (IRR: 2.03; 95% CI: 1.07-3.86). DISCUSSION: In a sample from a large, prospective cohort of WTC RRWV we found a lung cancer incidence rate that was similar to that expected of a WTC- and occupationally-unexposed cohort with similar individual risk profiles. Guideline-concordant lung cancer surveillance and periodic evaluations of population-level lung cancer risk should continue in this group.

Temporal Aspects of the Association between Exposure to the World Trade Center Disaster and Risk of Cutaneous Melanoma.

Rescue/recovery workers who responded to the World Trade Center (WTC) attacks were exposed to known/suspected carcinogens. Studies have identified a trend toward an elevated risk of cutaneous melanoma in this population; however, few found significant increases. Furthermore, temporal aspects of the association have not been investigated. A total of 44,540 non-Hispanic White workers from the WTC Combined Rescue/Recovery Cohort were studied between March 12, 2002 and December 31, 2015. Cancer data were obtained through linkages with 13 state registries. Poisson regression was used to estimate hazard ratios and 95% confidence intervals using the New York State population as the reference; change points in hazard ratios were estimated using profile likelihood. We observed 247 incident cases of melanoma. No increase in incidence was detected during 2002-2004. From 2005 to 2015, the hazard ratio was 1.34 (95% confidence interval = 1.18-1.52). A dose‒response relationship was observed by arrival time at the WTC site. Risk was elevated just over 3 years after the attacks. Whereas WTC-related exposures to UVR or other agents might have contributed to this result, exposures other than those at the WTC site, enhanced medical surveillance, and lack of a control group with a similar proportion of rescue/recovery workers cannot be discounted. Our results support continued study of this population for melanoma.

Cancer Incidence in World Trade Center Rescue and Recovery Workers: 14 Years of Follow-Up.

BACKGROUND: Statistically significantly increased cancer incidence has been reported from 3 cohorts of World Trade Center (WTC) disaster rescue and recovery workers. We pooled data across these cohorts to address ongoing public concerns regarding cancer risk 14 years after WTC exposure. METHODS: From a combined deduplicated cohort of 69 102 WTC rescue and recovery workers, a sample of 57 402 workers enrolled before 2009 and followed through 2015 was studied. Invasive cancers diagnosed in 2002-2015 were identified from 13 state cancer registries. Standardized incidence ratios (SIRs) were used to assess cancer incidence. Adjusted hazard ratios (aHRs) were estimated from Cox regression to examine associations between WTC exposures and cancer risk. RESULTS: Of the 3611 incident cancers identified, 3236 were reported as first-time primary (FP) cancers, with an accumulated 649 724 and 624 620 person-years of follow-up, respectively. Incidence for combined FP cancers was below expectation (SIR = 0.96, 95% confidence interval [CI] = 0.93 to 0.99). Statistically significantly elevated SIRs were observed for melanoma-skin (SIR = 1.43, 95% CI = 1.24 to 1.64), prostate (SIR = 1.19, 95% CI = 1.11 to 1.26), thyroid (SIR = 1.81, 95% CI = 1.57 to 2.09), and tonsil (SIR = 1.40, 95% CI = 1.00 to 1.91) cancer. Those arriving on September 11 had statistically significantly higher aHRs than those arriving after September 17, 2001, for prostate (aHR = 1.61, 95% CI = 1.33 to 1.95) and thyroid (aHR = 1.77, 95% CI = 1.11 to 2.81) cancers, with a statistically significant exposure-response trend for both. CONCLUSIONS: In the largest cohort of 9/11 rescue and recovery workers ever studied, overall cancer incidence was lower than expected, and intensity of WTC exposure was associated with increased risk for specific cancer sites, demonstrating the value of long-term follow-up studies after environmental disasters.

Temporal association of prostate cancer incidence with World Trade Center rescue/recovery work.

BACKGROUND: The World Trade Center (WTC) attacks on 11 September 2001 created a hazardous environment with known and suspected carcinogens. Previous studies have identified an increased risk of prostate cancer in responder cohorts compared with the general male population. OBJECTIVES: To estimate the length of time to prostate cancer among WTC rescue/recovery workers by determining specific time periods during which the risk was significantly elevated. METHODS: Person-time accruals began 6 months after enrolment into a WTC cohort and ended at death or 12/31/2015. Cancer data were obtained through linkages with 13 state cancer registries. New York State was the comparison population. We used Poisson regression to estimate hazard ratios and 95% CIs; change points in rate ratios were estimated using profile likelihood. RESULTS: The analytic cohort included 54 394 male rescue/recovery workers. We observed 1120 incident prostate cancer cases. During 2002-2006, no association with WTC exposure was detected. Beginning in 2007, a 24% increased risk (HR: 1.24, 95% CI 1.16 to 1.32) was observed among WTC rescue/recovery workers when compared with New York State. Comparing those who arrived earliest at the disaster site on the morning of 11 September 2001 or any time on 12 September 2001 to those who first arrived later, we observed a positive, monotonic, dose-response association in the early (2002-2006) and late (2007-2015) periods. CONCLUSIONS: Risk of prostate cancer was significantly elevated beginning in 2007 in the WTC combined rescue/recovery cohort. While unique exposures at the disaster site might have contributed to the observed effect, screening practices including routine prostate specific antigen screening cannot be discounted.

Cancer survival among World Trade Center rescue and recovery workers: A collaborative cohort study.

BACKGROUND: World Trade Center (WTC)-exposed responders may be eligible to receive no-cost medical monitoring and treatment for certified conditions, including cancer. The survival of responders with cancer has not previously been investigated. METHODS: This study compared the estimated relative survival of WTC-exposed responders who developed cancer while enrolled in two WTC medical monitoring and treatment programs in New York City (WTC-MMTP responders) and WTC-exposed responders not enrolled (WTC-non-MMTP responders) to non-responders from New York State (NYS-non-responders), all restricted to the 11-southernmost NYS counties, where most responders resided. Parametric survival models estimated cancer-specific and all-cause mortality. Follow-up ended at death or on December 31, 2016. RESULTS: From January 1, 2005 to December 31, 2016, there were 2,037 cancer cases and 303 deaths (248 cancer-related deaths) among WTC-MMTP responders, 564 cancer cases, and 143 deaths (106 cancer-related deaths) among WTC-non-MMTP responders, and 574,075 cancer cases and 224,040 deaths (158,645 cancer-related deaths) among the NYS-non-responder population. Comparing WTC-MMTP responders with NYS-non-responders, the cancer-specific mortality hazard ratio (HR) was 0.72 (95% confidence interval [CI] = 0.64-0.82), and all-cause mortality HR was 0.64 (95% CI = 0.58-0.72). The cancer-specific HR was 0.94 (95% CI = 0.78-1.14), and all-cause mortality HR was 0.93 (95% CI = 0.79-1.10) comparing WTC-non-MMTP responders to the NYS-non-responder population. CONCLUSIONS: WTC-MMTP responders had lower mortality compared with NYS-non-responders, after controlling for demographic factors and temporal trends. There may be survival benefits from no-out-of-pocket-cost medical care which could have important implications for healthcare policy, however, other occupational and socioeconomic factors could have contributed to some of the observed survival advantage.

Impact of healthcare services on thyroid cancer incidence among World Trade Center-exposed rescue and recovery workers.

BACKGROUND: A recent study of World Trade Center (WTC)-exposed firefighters and emergency medical service workers demonstrated that elevated thyroid cancer incidence may be attributable to frequent medical testing, resulting in the identification of asymptomatic tumors. We expand on that study by comparing the incidence of thyroid cancer among three groups: WTC-exposed rescue/recovery workers enrolled in a New York State (NYS) WTC-medical monitoring and treatment program (MMTP); WTC-exposed rescue/recovery workers not enrolled in an MMTP (non-MMTP); and the NYS population. METHODS: Person-time began on 9/12/2001 or at enrollment in a WTC cohort and ended at death or on 12/31/2015. Cancer data were obtained through linkages with 13 state cancer registries. We used Poisson regression to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for MMTP and non-MMTP participants. NYS rates were used as the reference. To estimate potential changes over time in WTC-associated risk, change points in RRs were estimated using profile likelihood. RESULTS: The thyroid cancer incidence rate among MMTP participants was more than twice that of NYS population rates (RR = 2.31; 95% CI = 2.00-2.68). Non-MMTP participants had a risk similar to NYS (RR = 0.96; 95% CI = 0.72-1.28). We observed no change points in the follow-up period. CONCLUSION: Our findings support the hypothesis that no-cost screening (a benefit provided by WTC-MMTPs) is associated with elevated identification of thyroid cancer. Given the high survival rate for thyroid cancer, it is important to weigh the costs and benefits of treatment, as many of these cancers were asymptomatic and may have been detected incidentally.

Development and Validation of a Clinical Frailty Index for the World Trade Center General Responder Cohort.

Objectives: To develop and validate a clinical frailty index to characterize aging among responders to the 9/11 World Trade Center (WTC) attacks. Methods: This study was conducted on health monitoring data on a sample of 6197 responders. A clinical frailty index, WTC FI-Clinical, was developed according to the cumulative deficit model of frailty. The validity of the resulting index was assessed using all-cause mortality as an endpoint. Its association with various cohort characteristics was evaluated. Results: The sample's median age was 51 years. Thirty items were selected for inclusion in the index. It showed a strong correlation with age, as well as significant adjusted associations with mortality, 9/11 exposure severity, sex, race, pre-9/11 occupation, education, and smoking status. Discussion: The WTC FI-Clinical highlights effects of certain risk factors on aging within the 9/11 responder cohort. It will serve as a useful instrument for monitoring and tracking frailty within this cohort.

Combining Three Cohorts of World Trade Center Rescue/Recovery Workers for Assessing Cancer Incidence and Mortality.

Three cohorts including the Fire Department of the City of New York (FDNY), the World Trade Center Health Registry (WTCHR), and the General Responder Cohort (GRC), each funded by the World Trade Center Health Program have reported associations between WTC-exposures and cancer. Results have generally been consistent with effect estimates for excess incidence for all cancers ranging from 6 to 14% above background rates. Pooling would increase sample size and de-duplicate cases between the cohorts. However, pooling required time consuming steps: obtaining Institutional Review Board (IRB) approvals and legal agreements from entities involved; establishing an honest broker for managing the data; de-duplicating the pooled cohort files; applying to State Cancer Registries (SCRs) for matched cancer cases; and finalizing analysis data files. Obtaining SCR data use agreements ranged from 6.5 to 114.5 weeks with six states requiring >20 weeks. Records from FDNY (n = 16,221), WTCHR (n = 29,372), and GRC (n = 33,427) were combined de-duplicated resulting in 69,102 unique individuals. Overall, 7894 cancer tumors were matched to the pooled cohort, increasing the number cancers by as much as 58% compared to previous analyses. Pooling resulted in a coherent resource for future research for studies on rare cancers and mortality, with more representative of occupations and WTC- exposure.

Retrospective Assessment of Risk Factors for Head and Neck Cancer Among World Trade Center General Responders.

Objective: To assess the reliability of a questionnaire designed to reconstruct risk factors for head and neck cancer relative to the 9/11 World Trade Center (WTC) response and over the lifetime. Methods: As part of a nested case-control study, 200 WTC Health Program (WTCHP) General Responder Cohort (GRC) members completed a newly-developed study questionnaire via telephone (with a trained interviewer) or online (self-administered). We assessed agreement between measures of tobacco and alcohol use in our questionnaire results and data collected previously during WTCHP-GRC monitoring visits using Cohens Kappa (κ) and intraclass correlation coefficient (ICC) for categorical and continuous measures, respectively. We compared agreement by disease status, survey mode, and year of WTCHP enrollment. Results: We observed high agreement between measures of lifetime, pre-WTC, and post-WTC smoking prevalence (all κ > 0.85) and smoking duration (all ICC > 0.84). There was moderate agreement between measures of smoking frequency (ICC: 0.61-0.73). Agreement between measures of smoking frequency, but not duration, differed by disease status, and agreement between smoking measures was higher for participants who completed our survey by phone than by web. Among cases, there were no differences based on enrollment in the WTCHP before or after diagnosis. Conclusion: Agreement between measures was generally high, although potential reporting bias and a mode effect that should be considered when interpreting analyses of self-reported data in this population; however differential misclassification appears to be minimal. Our questionnaire may be useful for future studies examining similar behavioral risk factors among disaster-exposed populations.

Cancer in General Responders Participating in World Trade Center Health Programs, 2003-2013.

BACKGROUND: Following the September 11, 2001, attacks on the World Trade Center (WTC), thousands of workers were exposed to an array of toxins known to cause adverse health effects, including cancer. This study evaluates cancer incidence in the WTC Health Program General Responder Cohort occurring within 12 years post exposure. METHODS: The study population consisted of 28 729 members of the General Responder Cohort enrolled from cohort inception, July 2002 to December 31, 2013. Standardized incidence ratios (SIRs) were calculated with cancer case inclusion and follow-up starting post September 11, 2001 (unrestricted) and, alternatively, to account for selection bias, with case inclusion and follow-up starting 6 months after enrollment in the WTC Health Program (restricted). Case ascertainment was based on linkage with six state cancer registries. Under the restricted criterion, hazard ratios were estimated using multivariable Cox proportional hazards models for all cancer sites combined and for prostate cancer. RESULTS: Restricted analyses identified 1072 cancers in 999 responders, with elevations in cancer incidence for all cancer sites combined (SIR = 1.09, 95% confidence interval [CI] = 1.02 to 1.16), prostate cancer (SIR = 1.25, 95% CI = 1.11 to 1.40), thyroid cancer (SIR = 2.19, 95% CI = 1.71 to 2.75), and leukemia (SIR = 1.41, 95% CI = 1.01 to 1.92). Cancer incidence was not associated with any WTC exposure index (composite or individual) for all cancer sites combined or for prostate cancer. CONCLUSION: Our analyses show statistically significant elevations in cancer incidence for all cancer sites combined and for prostate and thyroid cancers and leukemia. Multivariable analyses show no association with magnitude or type of exposure.

Risk factors for head and neck cancer in the World Trade Center Health Program General Responder Cohort: results from a nested case-control study.

OBJECTIVES: Head and neck cancers (HNCs) may be among the health consequences of involvement in the World Trade Center (WTC) response on and after 11 September 2001. We conducted a nested case-control study of WTC Health Program (WTCHP) general responders to examine the effects of WTC exposures and behavioural risk factors on HNC. METHODS: We enrolled 64 cases and 136 controls, matched on age, sex and race/ethnicity within risk sets. We assessed tobacco and alcohol use, sexual activity, and occupational exposures prior to, during and after WTC exposure until case diagnosis via questionnaire. We obtained WTC exposure information (duration (first to last day), total days and location of work) from the WTCHP General Responder Data Center. We assessed associations with HNC, and interaction among exposures, using conditional logistic regression. RESULTS: Responders in protective services versus other occupations had increased odds (OR: 2.51, 95% CI 1.09 to 5.82) of HNC. Among those in non-protective services occupations, arriving to the WTC effort on versus after 11 September 2001 was significantly associated with HNC (OR: 3.77, 95% CI 1.00 to 14.11). Duration of work was not significantly associated with HNC. Lifetime and post-WTC years of cigarette smoking and post-WTC number of sex partners were positively and significantly associated with HNC, while alcohol consumption was not. CONCLUSIONS: These findings suggest opportunities for HNC risk factor mitigation (eg, smoking cessation, human papillomavirus vaccination) and contribute to a risk factor profile which may assist WTCHP clinicians with identifying high-risk responders and improve detection and treatment outcomes in this population.

Excess HPV-related head and neck cancer in the world trade center health program general responder cohort.

The World Trade Center (WTC) attacks exposed rescue and recovery workers to a complex mix of toxicants, including carcinogens. our study compared site-specific cancer incidence of head and neck cancers (HNC) from 2003 through 2012 among 33,809 consented WTC General Responder Cohort (GRC) members to the New Jersey State Cancer Registry, using standardized incidence ratios (SIRs). HNC grouped using SEER ICD-O-3 codes into HPV-related (oropharyngeal) and non-related (other oral-nasal; laryngeal) tumors based on anatomical site. For the 73 GRC members identified with HNC, proportional hazard regression assessed the relationship between WTC exposure and other socio-demographic characteristics. An overall excess of HNC was not observed (SIR = 1.00, 95% CI: 0.78, 1.25) but excess cancer was seen in the latest observation period (2009-2012: SIR = 1.4; 95% CI: 1.01, 1.89). A similar temporal pattern was seen for HPV-related oropharyngeal cancer and laryngeal cancer, but not for non-HPV-related sites (oral-nasal cancer). HNC was significantly associated with increasing age (8% per year, 95% CI: 5%, 12%), non-Hispanic white ethnic group-ethnicity (hazard ratio (HR) = 3.51, 95 CI: 1.49, 8.27); there was a borderline association with the 9/11 occupation of military/protective services vs. others (HR = 1.83 95% CI: 0.99, 3.38; p = 0.0504). Caution is needed in interpreting these results given the small number of cases, potential for surveillance bias, and long latency for most cancers. Our findings highlight the need to examine the potentially carcinogenic effects of WTC exposure in the context of other strong risk factors, and the need for continued medical monitoring of WTC responders.

Development of a Physiological Frailty Index for the World Trade Center General Responder Cohort.

Responders to the 9/11/2001 WTC attacks were exposed to multiple toxic pollutants. Since 2002, the health of the responder cohort has been continuously tracked by the WTC Health Monitoring Program. However, no assessments have been made of frailty, an important health metric given the current average age of the WTC responder cohort (55 years). In this study, we use laboratory test results and other physiological parameters to construct a physiological frailty index (FI-Lab) for this cohort. The study sample comprised responders aged 40 years or older who completed a health monitoring visit at Mount Sinai Center within the past 5 years. For each subject, FI-Lab was computed as the proportion of 20 physiological parameters (lab tests, pulmonary function, and blood pressure) on which the subject had abnormal values. Using negative binomial regression models, we tested FI-Lab's association with the SF-12 wellbeing score and various demographic characteristics. FI-Lab showed strong associations with the physical and mental components of the SF-12 as well as age, race, and smoking status. Using a cutoff of 0.25 to define presence of physiological/preclinical frailty, we found frailty prevalence in the study sample to be approximately 12%. This study demonstrates the feasibility of assessing preclinical frailty in the WTC responder cohort.

Uranium associations with kidney outcomes vary by urine concentration adjustment method.

Uranium is a ubiquitous metal that is nephrotoxic at high doses. Few epidemiologic studies have examined the kidney filtration impact of chronic environmental exposure. In 684 lead workers environmentally exposed to uranium, multiple linear regression was used to examine associations of uranium measured in a 4-h urine collection with measured creatinine clearance, serum creatinine- and cystatin-C-based estimated glomerular filtration rates, and N-acetyl-ß-D-glucosaminidase (NAG). Three methods were utilized, in separate models, to adjust uranium levels for urine concentration--µg uranium/g creatinine; µg uranium/l and urine creatinine as separate covariates; and µg uranium/4 h. Median urine uranium levels were 0.07 µg/g creatinine and 0.02 µg/4 h and were highly correlated (rs=0.95). After adjustment, higher ln-urine uranium was associated with lower measured creatinine clearance and higher NAG in models that used urine creatinine to adjust for urine concentration but not in models that used total uranium excreted (µg/4 h). These results suggest that, in some instances, associations between urine toxicants and kidney outcomes may be statistical, due to the use of urine creatinine in both exposure and outcome metrics, rather than nephrotoxic. These findings support consideration of non-creatinine-based methods of adjustment for urine concentration in nephrotoxicant research.

Differences in urine cadmium associations with kidney outcomes based on serum creatinine and cystatin C.

Cadmium is a well-known nephrotoxicant; chronic exposure increases risk for chronic kidney disease. Recently, however, associations between urine cadmium and higher creatinine-based estimated glomerular filtration rate (eGFR) have been reported. Analyses utilizing alternate biomarkers of kidney function allow evaluation of potential mechanisms for these observations. We compared associations of urine cadmium with kidney function measures based on serum cystatin C to those with serum creatinine in 712 lead workers. Mean (standard deviation) molybdenum-corrected urine cadmium, Modification of Diet in Renal Disease (MDRD) eGFR and multi-variable cystatin C eGFR were 1.02 (0.65) µg/g creatinine, and 97.4 (19.2) and 112.0 (17.7) mL/min/1.73 m2, respectively. The eGFR measures were moderately correlated (rs=0.5; p<0.001). After adjustment, ln (urine cadmium) was not associated with serum cystatin-C-based measures. However, higher ln (urine cadmium) was associated with higher creatinine-based eGFRs including the MDRD and an equation incorporating serum cystatin C and creatinine (beta-coefficient=4.1 mL/min/1.73 m2; 95% confidence interval=1.6, 6.6). Urine creatinine was associated with serum creatinine-based but not cystatin-C-based eGFRs. These results support a biomarker-specific, rather than a kidney function, effect underlying the associations observed between higher urine cadmium and creatinine-based kidney function measures. Given the routine use of serum and urine creatinine in kidney and biomarker research, additional research to elucidate the mechanism(s) for these associations is essential.

Associations of low-level urine cadmium with kidney function in lead workers.

OBJECTIVES: Low-level cadmium exposure, resulting in, for example, urinary cadmium <2.0 µg/g creatinine, is widespread; recent data suggest nephrotoxicity even at these low levels. Few studies have examined the impact of low-level cadmium exposure in workers who are occupationally exposed to other nephrotoxicants such as lead. METHODS: We evaluated associations of urine cadmium, a measure of cumulative dose, with four glomerular filtration measures and N-acetyl-ß-D-glucosaminidase (NAG) in lead workers. Recent and cumulative lead doses were assessed via blood and tibia lead, respectively. RESULTS: In 712 lead workers, mean (SD) blood and tibia lead values, urine cadmium values and estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease equation were 23.1 (14.1) µg/dl, 26.6 (28.9) µg Pb/g bone mineral, 1.15 (0.66) µg/g creatinine and 97.4 (19.2) ml/min/1.73 m(2), respectively. After adjustment for age, sex, body mass index, urine creatinine, smoking, alcohol, education, annual income, diastolic blood pressure, current or former lead worker job status, new or returning study participant, and blood and tibia lead, higher ln-urine cadmium was associated with higher calculated creatinine clearance, eGFR (ß = 8.7 ml/min/1.73 m(2); 95% CI 5.4 to 12.1) and ln-NAG but lower serum creatinine. CONCLUSIONS: Potential explanations for these results include a normal physiological response in which urine cadmium levels reflect renal filtration, the impact of adjustment for urine dilution with creatinine in models of kidney outcomes, and cadmium-related hyperfiltration.

Occupational exposure to PCBs reduces striatal dopamine transporter densities only in women: a beta-CIT imaging study.

We hypothesize that occupational exposure to PCBs is associated with a reduction in central dopamine (DA) similar to changes previously seen in PCB exposed adult non-human primates. To test that hypothesis, we used [(123)I]beta-CIT SPECT imaging to estimate basal ganglia DA transporter density in former capacitor workers. Women, but not men, showed an inverse relationship between lipid-adjusted total serum PCB concentrations and DA transporter densities in the absence of differences in serum PCB concentrations. These sex differences may reflect age-related reductions in the levels of gonadal hormones since these hormones have been shown experimentally to alter response to DA neurotoxicants. These findings may aid in better understanding the roles that sex and age play in modifying central DA function following exposure, not only to PCBs, but also to other DA neurotoxicants as well as further elucidating the role of gonadal hormones in influencing the initiation and/or progression of neurodegenerative disorders.